Recently we have shown a positive correlation between the extent of F1 histone phosphorylation, quantitated by high resolution gel electrophoresis, and the rate of replication of a variety of normal and malignant tissues, including a hepatoma tissue culture line (HTC cells), and further have shown that this phosphorylation is temporally linked to DNA synthesis in HTC cells. Other studies, also involving HTC cells, have shown that the adenyl cyclase yields cAMP yields receptor protein yields protein kinase sequence (which may regulate histone phosphorylation) differs in several ways from liver. I have outlined a series of experiments which will use cultured cells to investigate further the relationship of histone phosphorylation to cell replication and the influence molecules such as hormones and cAMP might have on these processes. These studies are grouped in three categories: 1) The molecular nature of histone phosphorylation and its relation to DNA and cell replication; 2) Further characterization and isolation of the cAMP-receptor proteins and protein kinases of liver and three hepatic- derived cell lines (HTC, RLC and H4- II-E); and 3) The effect hormones and cAMP have on cell replication and enzyme induction, utilizing lines with different endogenous levels of cAMP, cAMP- receptor or protein kinase activities, as detected in No. 2. If histone phosphorylation regulates cell replication and if the enzyme responsible for this is subject to modulation by hormones or cAMP, we might expect to gain greater insight into means of controlling abnormal cell replication or malignancy.